Process for preparing 4-substituted thiazoles



Patented July 23, 1946 PROCESS Fort PREPARING 4-SUBSTITUTED THIAZOLES William. P. Utermohlen,

Jr., Kingsport, Tenn, assignorto Eastman Kodak Company, Rochester, N. Y., a corporation of New Jersey No Drawing. Application June 9., 1945, Serial No. 598,637

' 12 Claims. (01. 260--302) This invention relates to a process for preparing 4-substituted thiazoles. V

It. is known that 2,-amino-4-methylthiazole can. be prepared by condensing, thiourea with chloroacetone. In United Statesv Patent. 2,242,237,

dated May 20, 1941, the preparation of 2-aminothiazole from thiourea and :,B-di0hl0l08th3'l acetate. or a,p.-dibromoethyl. acetate is described. This patent. also discloses the. formationoi 2- amino-4-methylthiazole from thiourea and 00,1 dichloropropyl acetate. 4

I have now' found that thiourea and oL B-(ilchloroisopropyl acetate. condense to give 2-amino- 4-methylthiazole, a wholly unexpected end-product,1'in view 'of the prior reported condensation with mfl-d-ichloropropyl. acetate. If the cap-dichloropropyl acetate gives the -methyl deriva tive, it would be expected that the ccfi-CiiChlOlO- isopropy-lacetate would give the B-methyl derivatives. Not only have I, been able to prepare. 2i-amino-4emethylthiazole, but also other 4-substituted thiazoles using either ,p-dichloro or 11,}?- dibromo monocarboxylic esters with: other thioamides containing the --CS-NH2. group. g

It. is,v accordingly, an, object of my invention The ap-dihalogeno monocarboxylic esters of a the above general formula can be prepared by chlorinating or. brominating unsaturated esters, such as isopropenyl acetate (z-acetoxypropene- 1)., 2-acetoxy-hexene-l, 2- acetoxyheptene'-1, 2-

(chlorozrcetoxy) -hexene'-1,, 2 benzoyloxyhexene- 1, a-acet'oxystyrene, 2- (phenylacetoxy) -propene- 1, 2-acetoxy-3 phenylpropene-1, etc. Such unsaturated esters in which the acid radical is an tuted thiazoles. Other objects will become apparent hereinafter. p

In accordance with my invention,'I prepare 4-substituted thiazoles by condensing a thioamide containing the group with an 0;,fl-dihalogeno monocarboxylic ester 'of the following general formula:

zole's can be prepared, from thiobenzamide, 2-

phenyli-i-substituted thiazoles" can be prepared,- etc. When R represents methyl, a 4-methylthiazole is obtained, when R. represents ethyl, aa4z-eth ylthiazole isobtalned, when R; represents benzyl, a 4-benzylthiazole is obtained, when R represents phenyl, a l -phenylthiazole is obtained, etc.

. 2'5 to. provide a new process. for preparing 4-substip Syn. 19, 10 (1939) and references therein 2-amino-S-methylthiazole, on the other hand, -melts at 95 to 965 C'. and its acetyl derivative acetate radical (i. e. the acetoxy derivatives) can be prepared by condensing an appropriate ketone with ketene, in. the presence of sulfuric acid. See Gwynn and Degering, Journalof the American ChemicalSociety 64, 2216' 942). All the unsaturated esters can beprepared by. adding a monocarboxylic acid to the appropriate monosubstituted acetylene, in the presence of boron trifiuoride. See Hennion and Nieuwland, Journal of the American Chemical Societybfi, 1802 (1934). The following examples will serve to illustrate further the manner of practicing my invention.

88 g..('0.51' moi.) of fi dichloroisopropyl acetate were added dropwise, with stirring, to a solu- The upper dark oily layer which separated was separated-off, andthe'aqueous layer was extract;

, ed'withis'ever'al portions (about zoomr in all) of The dark oil and the benzene "extract were combined'and' partially-dried over solid so dium hydroxide. tered' off and the filtrate fractionally distilled in vacuo. After the benzene forerun, the '2-amino- 4-methy1thi'azole distilled over as a yellow 'oil which became asolid' upon standing. The 2 amino-4-intethylthiazole boiled at 103 C. at 1 mm. of Hg. pressure. {Theyieldwas 4'7 g. per cent) based on the u,,8'-dichloroisopropyl' acetate benzene.

The product melted atv 44 to 45f C. and an acetyl derivative prepared therefrom. melted at; 131,110 132; C. These melting-point .valuesyagreefwell with those previously, reported for z-amino l methylthiazole and its acetyl derivative (seeQrg,

melts at 224 C. See chem. lAbSt. 35, 458 (1941).

The sodium hydroxide was 111- Example 2.1-2 amino-st-rnethylthiazole l 133 g. (0.51 mol'.) of a,p-dibromoisopropyl acetate were condensed with thiourea exactl as in Example 1. The yield of 2-amino-4-methy1- thiazole was 54.5 g. (93 per cent) based on the I mp-dibromoisopropyl acetate. Using thioacetamide instead of thiourea, and

V 3 and 4, 2-acetoxyhexene- 1. 2-acetoxyheptene-1,

2 (chloroacetoxy hexene 1, -2 -benzoyloxynexene-l, u-acetoxystyrene, 2-(phenylacetoxy) prop'ene-l, 2-acetoxy-3-phenylpropene-1, etc. can be proceeding'exactly as in Example 1, a good'yield of 2,4-,dimethylthiazole can be obtained; with thiobenzamide, 2-phenyl-4-methylthiazole can be obtained, with thiophenylacetamide, 2-be'nzyl-4- methylthiazole can be obtained, etc. Using the dichloroester obtained by adding chlorine ;,to u-acetoxystyrene and condensing with thiourea,

2-amino-4-phenylthiazole can be obtained, using the dichloroester obtained by adding chlorine to acetoxystyrene and condensing withthioacetamide;2emethyl-4-phenylthiazo1e can be obtained, etc. 7 j i The following examples illustrate further the preparation ofthe dichloro and dibromoesters.

Example 3. u,c-dibromoisopropyl acetate 300 g; 3mo1.) .of isopropenyl acetatewere stirred andcoold to 0 C. 450 g, (2.8+ mol.) of bromine were directly added, dropwise, maintaining the temperature at 0 C. The'bromine' was immediately taken up. After addition of the bromine,the reaction mixture was fractionating in 'vacuo, using a total-condensation, variable takeoff still. Hydrogen bromide-and unchanged isopropenyl acetate were the first fractions to be distilled. The ,;8-dibromoisopropyl acetate was next obtained, andahigh boiling, residue was left behind. The e,p-dibromoisopropyl acetate boiled at 62 to 635 C. at 40 mm. of Hg. pressure. It

tilled and was'a strong lachrymator. N20/D 1.4714; D 20/20 1.6249. Bromine, calculated 61.5

per cent, found 61.8 per cent.

M, Example 4.cz,;3-diChlOT0iSOZPTOZJ2/l acetate 300g. (3' mol.); of isopropenyl acetate 4 were stirred and coo1ed-to;0' C. Chlorin gas was passed intothe cold'isopropenyl acetate maine taining the temperature {at 0 0., until somewhat more-than3 moles of chlorine-wereadded, Ni-

trogen gas was then blown throughthe reaction, mixture :to sweep out anyremaining free chlo-: rine; The -.-'mixture was then 'fractionated in; 3 vacuo as in Example 3, I-Iydrogenchlofiddun- 1 reacted isopropenylacetate, ap-dichloroisopropyl acetate and a high boiling residue was obtained The ,a,,c-dichloroisopropyl acetate boiled at 45 to 46? C.- at 41 mm. of 'Hg. pressure. It was afmobile liquid, colorless when freshl distilled and was a lachrymator.

1 *1.2158. Chlorine, calculated 41.5 ercent, found eujc per cent. In this exampleand in E'xample 3.,

the. conversions of isopropenyl acetate, to'the dp-dihalogenoisopropyl acetate were of. the order "of 40to 59 percent. 'The'yields, based on iso- 1 propenyl acetate, were much higher since'considerable'unreacted isopropenyl acetate was rcovi cred each case. f'

Ina manner similar to that shown inEXamp Ieswherein R and R1 each represents a n'i'embe'r 'sa.

chlorinatedor brominated to give dichloro or dibromo saturated esters.

What I claim a my invention and desire to be 4 V secured by Letters Patent of the United States is:

1. A process for preparing a 4- substituted thiazole comprising condensing a thioamide containing the --CSNH2 group with adihalogeno ester of the following general formula:

lected from the group consisting of alkyl, aralkyl and aryl'gr'oup's andX'representsa halogen selected from the group consisting of chlorine and bromine. i

2. A process for preparing] a 4-s'ubstituted thiazole comprising condensing 'a thioamide containing the 'CS -NH2 group with a S-dichI roisopropyl acetate.

. 3. A process for preparing a 4-substitut'ed thi 'azole comprising condensing-a thioamid containing the CSNH 2 group with ap-dibromoisop'ropyl acetate. g r

. comprising condensing tliio cetami'de with-bi was a mobile liquid, colorless :when freshly dis- 4. A process for preparing 2-amin'o-4 methyl thiazole comprising" cond' 0a,,3gdi0hlOIOiS0IJIODY1 acetate 5. A process for preparing 2-amino-4 -methyl a,B-dibroinoisopropylacetate;" r 4 f 6. A process for preparing'2,4 dimethylthiazole with a dihalogenofester of the f n wmgjeene 1 thiazole comprising" condensing thiour'eaiwith' wherein R and R1 each represents am er sc lected from the'grou'p consisting of alkyl, ara kyl and aryl groups andKrsPlfi enE a. halogen selected from the group consisting of chlorine and bromine.

N 20/D 1.4344; D 20/20 um) thioacetamidey-with pedibromoisopropyl "10; A' process for preparing-zzeamino, thiazole. comprising .conde'nsing, inian aqueous 8. YA process for preparing: a'.4esubstituted:thi-

azole comprising condensing-yin, anaqueous medi* um, a thioamide containing; the -'-.-CS?NH2 group with afi dichloroisopropylacetate..

- .9. Aprocessforpreparing a 4- s ubstituted thifazole comprising condensingfin anfaqueousmedF azole comprisingv condensing, in an .aq'ueou'smedie acetate; WILLIAM. P. -'U'I'ERMOI- ILEN JR ensing thio ur'ea with .-1'1 2.,A processifor' preparing ,2,4-dimetliyithi A V 

